DeGroot Melisa S, Williams Byron, Chang Timothy Y, Maas Gamboa Maria L, Larus Isabel, Fromme J Christopher, Liu Jun
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853.
bioRxiv. 2023 Jan 8:2023.01.06.523017. doi: 10.1101/2023.01.06.523017.
Secreted modular calcium binding (SMOC) proteins are conserved matricellular proteins found in organisms from to humans. SMOC homologs characteristically contain one or two extracellular calcium (EC) binding domain(s) and one or two thyroglobulin type-1 (TY) domain(s). SMOC proteins in and Xenopus have been found to interact with cell surface heparan sulfate protein glycans (HSPGs) to exert both positive and negative influences on the conserved bone morphogenetic protein (BMP) signaling pathway. In this study, we used a combination of biochemical, structural modeling, and molecular genetic approaches to dissect the functions of the sole SMOC protein in . We showed that SMOC-1 binds LON-2/glypican, as well as the mature domain of DBL-1/BMP. Moreover, SMOC-1 can simultaneously bind LON-2/glypican and DBL-1/BMP. The interaction between SMOC-1 and LON-2/glypican is mediated by the EC domain of SMOC-1, while the interaction between SMOC-1 and DBL-1/BMP involves full-length SMOC-1. We further showed that while SMOC-1(EC) is sufficient to promote BMP signaling when overexpressed, both the EC and TY domains are required for SMOC-1 function at the endogenous locus. Finally, when overexpressed, SMOC-1 can promote BMP signaling in the absence of LON-2/glypican. Taken together, our findings led to a model where SMOC-1 functions both negatively in a LON-2-dependent manner and positively in a LON-2-independent manner to regulate BMP signaling. Our work provides a mechanistic basis for how the evolutionarily conserved SMOC proteins regulate BMP signaling.
分泌型模块化钙结合（SMOC）蛋白是在从[具体生物]到人类的生物体中发现的保守的基质细胞蛋白。SMOC同源物通常包含一个或两个细胞外钙（EC）结合结构域和一个或两个甲状腺球蛋白1型（TY）结构域。已发现[具体生物]和非洲爪蟾中的SMOC蛋白与细胞表面硫酸乙酰肝素蛋白聚糖（HSPG）相互作用，对保守的骨形态发生蛋白（BMP）信号通路产生正负两方面的影响。在本研究中，我们结合生化、结构建模和分子遗传学方法来剖析[具体生物]中唯一的SMOC蛋白的功能。我们表明SMOC-1结合LON-2/磷脂酰肌醇蛋白聚糖，以及DBL-1/BMP的成熟结构域。此外，SMOC-1可以同时结合LON-2/磷脂酰肌醇蛋白聚糖和DBL-1/BMP。SMOC-1与LON-2/磷脂酰肌醇蛋白聚糖之间的相互作用由SMOC-1的EC结构域介导，而SMOC-1与DBL-1/BMP之间的相互作用涉及全长SMOC-1。我们进一步表明，虽然SMOC-1（EC）过表达时足以促进BMP信号传导，但在内源位点，SMOC-1发挥功能需要EC和TY结构域。最后，过表达时，SMOC-1在没有LON-2/磷脂酰肌醇蛋白聚糖的情况下也可以促进BMP信号传导。综上所述，我们的研究结果得出了一个模型，其中SMOC-1以LON-2依赖性方式发挥负向作用，并以LON-2非依赖性方式发挥正向作用来调节BMP信号传导。我们的工作为进化上保守的SMOC蛋白如何调节BMP信号传导提供了一个机制基础。
